Sarcoidosis Lancet 2013

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www.thelancet.com Published online October 1, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60680-7 1

SarcoidosisDominique Valeyre, Antje Prasse, Hilario Nunes, Yurdagul Uzunhan, Pierre-Yves Brillet, Joachim Mller-Quernheim

Sarcoidosis is a systemic disease of unknown cause that is characterised by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Studies show that sarcoidosis might be the result of an exaggerated granulomatous reaction after exposure to unidenti ed antigens in individuals who are genetically susceptible. Several new insights have been made, particularly with regards to the diagnosis and care of some important manifestations of sarcoidosis. The indications for endobronchial ultrasound in diagnosis and for PET in the assessment of in ammatory activity are now better speci ed. Recognition of unexplained persistent disabling symptoms, fatigue, small- bre neurological impairment, cognitive failure, and changes to health state and quality of life, has improved. Mortality in patients with sarcoidosis is higher than that of the general population, mainly due to pulmonary brosis. Predicted advances for the future are nding the cause of sarcoidosis, and the elucidation of relevant biomarkers, reliable endpoints, and new e cient treatments, particularly in patients with refractory sarcoidosis, lung brosis, and those with persistent disabling symptoms.

IntroductionSarcoidosis was recognised more than 120 years ago, and it remains a confusing disease with many grey areas.1 The cause of sarcoidosis is not known and diagnosis can be di cult and delayed from the diverse, nonspeci c, unusual, or initially misleading presentations. Many advances have been made since the previous seminar on sarcoidosis in The Lancet,2 and the publication of other reviews.3,4 The indications for endobronchial ultrasound and for F- uorodeoxyglucose (F-FDG) PET have been elucidated further, and occurrence of persistent disabling symptoms such as fatigue, small- bre neuropathy, and cognitive dysfunction have been investigated further. Recognition of health status and quality-of-life im-pairments has improved. These advances and e orts to accurately assess the development of disease have provided a more comprehensive and personalised care for patients. However, important steps are still needed, such as more accurate biomarkers, improving diagnosis of some extrapulmonary localisations, validated endpoints, and treatments that are e cient in refractory cases. The most important step is to provide evidence on the cause of sarcoidosis.

EpidemiologySarcoidosis is a global disease, with a prevalence of about 4764 in 100 000, and an incidence of 10355 in 100 000 per year. The highest rates are reported in northern European and AfricanAmerican individuals, particularly in women, and lowest in Japan.5,6 Di erences in prevalence and incidence are linked to age, sex, ethnic origin, and geographical location. The disease can occur in both men and women, with 70% of patients aged 2545 years; however, in Europe and Japan, a second peak of incidence occurs in women older than 50 years of age.5,6 Sarcoidosis is rare in people younger than 15 years or older than 70 years. The female to male ratio is 120:175. Clinical expression of sarcoidosis is a ected by epidemiological and socioeconomic factors (appendix, p 1). Elderly-onset sarcoidosis is much more common in women, and in this disorder there is an

increased rate of change in general health and extra-pulmonary manifestations, particularly uveitis.7

The notion of environmental or transmissible agents having a causal role in sarcoidosis is lent support by temporal and spacetime clusters. Exposure to musty odours, insecticides, or to metal-processing industries are disease risk factors.8,9 A high incidence of sarcoidosis was reported in re ghters and other responders after the attacks on the World Trade Center in 2001.10,11 By contrast, a decreased risk has been linked to cigarette smoking.9 Sarcoidosis is usually sporadic, but is familial in 3696% of cases.12 A patients siblings have a higher risk of sarcoidosis than do parents, suggesting a recessive inheritance mode with incomplete penetrance.12 An 80-times increase in risk in monozygotic twins lends support to the idea that genetic factors might account for two-thirds of disease susceptibility.13

PathogenesisCausesThe exact cause of sarcoidosis is still not known. Many studies suggest that genetic susceptibility and environmental factors contribute to disease development.2,9,14 Immunologically, sarcoidosis is an exaggerated immune response to so far unidenti ed antigens. Data for the clinical heterogeneity of sarcoidosis strongly suggest that pathogen-associated molecular patterns of microbial antigens can trigger or amplify

Published OnlineOctober 1, 2013http://dx.doi.org/10.1016/S0140-6736(13)60680-7

Department of Pneumology (Prof D Valeyre MD, Prof H Nunes MD, Y Uzunhan MD) and Department of Radiology (Prof P-Y Brillet MD), Assistance Publique Hpitaux de Paris, Avicenne University Hospital, Bobigny, France; University Paris 13, Sorbonne Paris Cit, Bobigny, France (Prof D Valeyre, Prof H Nunes, Y Uzunhan, Prof P-Y Brillet); and Department of Pneumology, University Hospital, Freiburg, Germany (Prof A Prasse MD, Prof J Mller-Quernheim MD)

Correspondence to:Prof Dominique Valeyre, Service de Pneumologie, Hpital Avicenne, Bobigny 93009, [email protected]

Search strategy and selection criteria

We searched Medline and the Cochrane Library for reviews and original articles on sarcoidosis published in English from January 1, 2000, to January 1, 2013. We used the search term: sarcoidosis [MeSH] in combination with the following terms: diagnosis [MeSH], etiology [MeSH], epidemiology [MeSH], therapeutics [MeSH], or therapy [Subheading] or drug therapy [MeSH], follow-up studies [MeSH], or treatment outcome [MeSH]. We chose papers mainly from the past 5 years, although we did not exclude frequently referenced and highly regarded older reports. We also searched the reference lists of articles identi ed by this search strategy and selected those we judged to be relevant. We selected high-quality systematic reviews rather than individual studies.

See Online for appendix

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2 www.thelancet.com Published online October 1, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60680-7

in am mation. There is no evidence that sarcoidosis is an infectious disease; rather, it is an exaggerated immune response to pathogen-associated molecular patterns of killed and partly degraded mycobacteria and propionibacteria. Other organic and inorganic substances might also trigger sarcoidosis.15 The pathogen-associated molecular patterns trigger pattern-recognition receptors such as Toll-like receptors 2 and 9, C-type lectins, and NOD-like receptors.16,17 Mycobacteria and propionibacteria persist in macrophage phagosomes because their high lipid content in membranes makes them acid-fast, and many of their glycolipoproteins are not very soluble and resist degradation.

Chen and Moller15 used mass spectrometry to identify mycobacterial catalase-peroxidase as an antigen in Kveim test.18 Mycobacterial catalase-peroxidase was detected with immunoblotting in half of the tissue samples from patients with sarcoidosis, and further studies showed a mycobacterial catalase-peroxidase-speci c T-cell response to the protein in a similar proportion of patients with sarcoidosis.15 The possible role of mycobacterial antigens in the development of sarcoidosis is supported by many studies that detected mycobacterial pathogen-associated molecular patterns in tissues from patients with sarcoidosis substantially more often than in tissues from healthy individuals. Moreover, several di erent pathogen-associated molecular patterns from mycobacteria, such as mycobacterial catalase-peroxidase, superoxide dismutase A, and cord factor, induce pulmonary granuloma in mice.19,20 Products from propionibacteria, including DNA, have been found in higher percentages of patients with sarcoidosis, and many patients show a speci c T-cell response against propionibacterial-derived antigens.21 Notably, lysates from heat-killed propionibacteria can induce pulmonary granuloma in mice.22

Therefore, a microbial-induced host response promotes the aggregation and persistence of the non-degradable antigens, forming a nidus for granuloma formation.18 This formation causes sarcoid lesions through an exaggerated immune response from the close interaction between macrophages and T cells, which stimulate each other.23

In ammatory mechanismsWhereas alveolar macrophages from healthy donors suppress e ector T-cell responses, alveolar macrophages from patients with sarcoidosis have excellent antigen-presenting capacities. This increased response is caused by the upregulated expression and function of MHC-2 molecules and costimulatory molecules such as CD86, CD80, ICAM, and CD40.23 In the lung, these macrophages resemble dendritic cells,23 suggesting the ability to change from one type to another.

In acute sarcoidosis, the number of CD14 positive macrophages increasessuggesting the in ux of peripheral-blood monocyte-derived cells, which pro-liferate in situ.23 Notably, alveolar macrophages from patients with sarcoidosis are hyper-reactive to distinct

pattern-recognition receptor ligands,24 and have an increased TNF response when stimulated by TLR4.25 There is also an in ux of CXCR3-positive T-helper 1 (Th1) cells in organs with a sarcoid mani-festation, which is triggered by increased pulmonary production of CXCR3 chemokines such as CXCL10.26 In-situ activation of T lymphocytes causes production of interferon-, TNF, and interleukin 2, resulting in a Th1 immune response.23 Furthermore, activated macro-phages and dendritic cells shift the T-cell response towards Th1 di erentiation, and vice versa, Th1 cytokines activate antigen-presenting macrophages. Data suggest that although increased interleukin 17 production and Th17-positive cellular in ltrates have been reported, the role of Th17 cells in sarcoidosis is still to be de ned.27 Th1 immune response is exaggerated further because of the absence of negative immunological feedback signals deliveredeg, by regulatory T cells (Tregs). Low numbers of Tregs that have a reduced function have been reported in sarcoidosis, but their function could be restored by an experimental therapy with vasoactive intestinal peptide that leads to a reduction in the production of TNF by cells present in the bronchoalveolar lavage cells.28,29

Granuloma formationEpithelioid-cell-rich granulomas that are non-necrotising are thought to trap remnants of causative agents that cannot be further degraded. The reasons why sarcoidosis spontaneously resolves in some patients and progresses in others are poorly understood. In the progressive disease, the antigen is postulated to persist, thereby inducing a chronic immune response.18,23 However, in patients with spontaneous resolution, an increased release of the immunosuppressive cytokine transforming growth factor (TGF) has been noted,30 which lends supports to treatments manipulating the cytokine network with monoclonal antibodies to stop exaggerated proin ammatory cytokines such as TNF.31

GeneticsThe immunological events we discussed above depend on a predisposing genetic background. Speci c MHC-2 alleles can determine the course of the diseaseHLA-DRB1*03 predisposes to disease with spontaneous resolution and HLA-DRB1*14 or HLA-DRB1*15 are pre-disposing for a chronic course.32 Several studies on the MHC-2 genes show clear associations of the gene variations with sarcoidosis susceptibility, phenotype, and prognosis. An MHC-1 association is super imposed onto named MHC-2 associations, which a ect disease resolution or persistence.3335 Immune-cell activation is regulated at several stages by costimulatory mechanisms and the cytokine network. Several candidate gene-association studies have identi ed genetic loci and, most interestingly, many of these variant genes are involved in the regulation of the immune responseeg, Toll-like receptors,36 MHC-2 transactivators,33 and

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others. However, replication is still needed for many of those studies.

Genome-wide association studies have identi ed previously unsuspected loci that increase sarcoidosis susceptibility: BTNL2,37 ANXA11,38 and others. Although these genes have a role in the immune system, the mechanisms that underlie the newly identi ed associations are often not obvious, but BTNL2 could function as a costimulatory molecule.39

These ndings show sarcoidosis is associated with a genetic risk pro le made up of many variant genes. Each of the known susceptibility genes confers an increased sarcoidosis risk, with an odds ratio of between 11 and 18, but these genes will substantially a ect disease predisposition when combined. New approaches such as transcriptome or miRNA analysis should be used to identify speci c signatures of clinical usefulness. With these techniques, subphenotype-speci c gene expression patterns have been identi ed for brotic sarcoidosis,40 and interactive gene networks have been discovered that include unexpected but important genes such as those for the matrix metalloproteinases.41 Signatures for protein expression, mRNA transcription, or miRNA obtained with these techniques might be useful for di erential diagnoses or to identify subphenotypes of prognostic relevance such as treatment resistance. Together, these data suggest the existence of several disorders that are diagnosed as sarcoidosis.

Di erences in genetic backgrounds, immunological responses, and causative agents that are so far unrecognised will lead to the de nition of subsyndromes, which will probably need di erent therapeutic approaches. Studies of those targets are in progress.

DiagnosisThere have been several new insights in the diagnosis of sarcoidosis ( gure 1). Endobronchial ultrasound-guided trans bronchial needle aspiration is a highly e ective investigation for mediastinal and hilar lymphadenopathy, and can prevent the need for 87% of mediastinoscopies.42

Moreover, rapid on-site assessment by well trained cytologists provides su cient diagnostic information for the bronchoscopist about the need for additional lymph-node passes or transbronchial lung biopsy samples,43 and might be an alternative to doing endobronchial and transbronchial lung biopsy rst. F-FDG PET can be used to accurately assess in ammatory activity4447 in patients with unexplained, persistent, disabling symptoms without serological in ammatory activity, and can help to predict pulmonary deterioration at 1 year, and the pulmonary improvement expected after treatment. Inhibition of the physiological myocardial uptake with heparin injection or appropriate diets can enable the detection of cardiac sarcoidosis active lesions with F-FDG PET.48,49 Knowledge of pulmonary hypertension, cardiac involvement, small- bre neuropathy, fatigue,

Figure 1: Diagnosis of sarcoidosisSolid line indicates usual practice. Dotted line indicates alternative practice. BHL=bilateral hilar lymphadenopathy. EPL=extrapulmonary localisations. BB=bronchial biopsy. BAL=bronchoalveolar lavage. TBB=transbronchial biopsy. ROSE=rapid on-site cytological examination. F-FDG=F- uorodeoxyglucose.

Symptoms consistent with sarcoidosis

EPLs

Stage 3 Stage 2

Yes

BALNo Endobronchialultrasound and ROSE

YesNo No

Symptomatic BHL

Endoscopy BB, BAL, TBBOther EPLs

Normal chest radiograph

Skin; lymph node;conjunctival nodule

Minor salivarygland biopsy

Yes

Biopsy sample with granulomas (or BAL-positive)

Sarcoidosis

18F-FDG PET

Endoscopy BB, BAL

Abnormal chest radiograph

Eliminate other diseases including tuberculosis;berylliosis

Lfgrens and Heerfordtssyndromes; BHL and uveitis;asymptomatic BHL

Follow-up

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cognitive failure, and impaired health status and quality of life has improved.5053

Initial manifestations of sarcoidosis vary with race, sex, and age (appendix p 1).1 The most common manifestations are persistent cough, localisation of disease in the skin, eye, and peripheral lymph nodes, erythema nodosum, fatigue, and incidental abnormal chest radiograph. Skin localisation of disease usually leads to a rapid diagnosis; however, diagnosis can be slow because persistent non-speci c respiratory symptoms and rare manifestations often do not prompt the need for a chest radiograph.54

The three criteria for diagnosis are: clinical and radiological presentation, evidence of non-caseating granulomas, and evidence of no alternative diseases.1 Con dence in diagnosis can be strengthened with time. The respective weight of each criterion varies with presentation as noted in the following example scenarios. In our rst scenario, diagnosis relies exclusively on a speci c presentation (eg, Lfgrens syndrome and Heerfordts syndrome), or it could match a few easily recognisable diagnoses (eg, bilateral perihilar masses on a chest radiograph where silicosis is di erentiated by history of reported occupation), making study of biopsy samples useless. In our second scenario, there is an initially isolated localisation or confusing element (eg, radiological pulmonary alveolar pattern) that is shared by other diseases, analysis of histological samples is crucial. In our third scenarioie, granulomatous disease that is con rmed easily with analysis of histological samplesthe elimination of all other granulomatoses (eg, tuberculosis or berylliosis) is crucial.

The most common diagnostic signs are bilateral intrathoracic hilar lymphadenopathy or di use micronodular pulmonary in ltration at chest radiograph, associated with a typical lymphatic distribution or a galaxy sign on CT ( gure 2),55 and the presence of some extrapulmonary localisations of diseaseeg, in the eye and skin (table 1, appendix p 1). If less characteristic clinical or radiological manifestations predominate, the combined presence of these signs substantially increases the amount of diagnostic con dence.68

Diagnosis of sarcoidosis is improved by a biopsy sample that shows non-caseating epithelioid granulomas. One positive biopsy analysis result is usually su cient. Biopsy sample analysis is recommended before treatment. However, biopsy sampling is not needed for the diagnosis of Lfgrens syndrome and, according to many physicians, for typical bilateral hilar lymphadenopathy that is asymptomatic or associated with uveitis, or for advanced cases of sarcoidosis with no e ect on treatment. The best biopsy site depends on accessibility, safety, and potential yield of the procedure according to presentation ( gure 1). Biopsy samples of super cial lesionsskin lesions other than erythema nodosum, palpable peripheral lymph node, or visible conjunctival nodulesshould be considered before other sites. If none of these factors are present, then exible bronchoscopy with endobronchial and transbronchial lung biopsy and endobronchial ultrasound are corner stone investigations. Bronchoalveolar lavage shows a moderate (2050%) lymphocytosis in 80% cases of sarcoidosis and a T lymphocyte CD4:CD8 ratio higher than 35 in 50% of cases, and this technique could be used to support sarcoidosis diagnosis.69 Analysis of a biopsy sample of minor salivary gland is useful when previous samples have failed, or when no target is easily accessible.

Di erential diagnoses that should be considered are: infections, particularly tuberculosis; occupationally induced, environmentally induced, and drug-induced granulomatosis; common variable immune de ciency; Blaus syndrome; sarcoid-like reactions in cancers and lymphomas, and other idiopathic granulomatosis (appendix p 3). Diagnosis of common variable immune de ciency relies on hypogammaglobulinaemia,70 and the diagnosis of chronic pulmonary berylliosis is dependent on a focused questionnaire and on beryllium hyper sensitivity.71

All speci c manifestations of sarcoidosis, even when asymptomatic, should be recognised through diagnostic work-up (appendix p 2). General symptoms, health status, and quality of life should be assessed.

Figure 2: CT of typical features of lung sarcoidosis(A) Shows typical perilymphatic distribution of micronodules with ssural spreading. (B) Shows typical nodules with irregular margins and satellite micronodules known as the galaxy sign.

A B

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The most common symptom of mediastinalpulmonary manifestations of sarcoidosis is a persistent cough. Dyspnoea, which is rare in the early stages of the disease, becomes more frequent later on. Wheezing and haemoptysis are infrequent. Crackles are rare. Chest radiographs, abnormal in 90% of cases, show lymphadenopathy in 2565%, di use pulmonary in ltration in 40%, and pulmonary brosis in 5% of patients at presentation. Scadding radiographical staging classi es disease as stage 1 (lymphadenopathy alone), stage 2 (pulmonary in ltration with lymphadenopathy), stage 3 (pulmonary in ltration without lymphadenopathy), and stage 4 (pulmonary brosis), although this scale shows poor interobserver agreement, particularly for stage 4 disease.1,72 Thoracic CT, although not always needed, helps when there is a di cult diagnosis or complications, particularly pulmonary brosis.55,73 CT can show the e ects of granulomatous and brous lung lesions respective contributions on disease ( gure 3A),74 and can be used to reliably assess disease severity. F-FDG PET accurately shows active in ammation in stage 4.44

Volume restriction or air ow limitation indicates lung

and airway involvement, while a decreased di usion capacity of carbon monoxide and an abnormal ow volume curve are most typical. The 6 min walk distance is often reduced in sarcoidosis and is correlated with results from the St Georges respiratory questionnaire and forced vital capacity assessments.75 Bronchial endoscopy is used to access granulomas and to visualise proximal airways.

In particular situations, cardiopulmonary exercise testing could help to detect impaired pulmonary gas exchange during exercise in patients with unexplained disabling symptoms, and normal results for spirometry and di usion capacity of carbon monoxide.76,77 Cardiopulmonary exercise testing can also help investigators to understand mechanisms behind dyspnoea of unclear origin and assess overall disease e ect,76,77 and can be a predictor for the decline in pulmonary function and for prolonged immunosuppressive treatment.78,79 The combination of pulmonary function tests, endoscopy, and CT allow the assessment of causes of air ow limitationsbronchial mucosal nodules, bronchial distortion and narrowing

Prevalence (%) Symptoms Investigations

Skin56 ~15 Papules, nodules, plaques, scar sarcoidosis, lupus pernio, subcutaneous sarcoidosis

Biopsy (except for in lupus pernio)

Peripheral lymphadenopathy1,57 1020 Mostly cervical or supraclavicular; inguinal, axillary, epitrochlear, or submandibular lymph node sites also possible; painless and mobile

Biopsy

Eye58,59 1030 Anterior, intermediate, or posterior uveitis; retinal vascular change; conjunctival nodules; lacrimal gland enlargement

Systematic ophthalmologist examination, slit-lamp examination, uorescein angiography

Liver60 2030 Often symptom-free; abnormal liver function tests in 2030% of patients; hepatomegaly; rarely hepatic insu ciency, chronic intrahepatic cholestasis, or portal hypertension

Systematic liver function tests, abdominal echography and CT, biopsy recommended if moderate or severe abnormalities on liver tests

Spleen57 ~10 Splenomegaly; rarely, pain or pancytopenia; very rarely, splenic rupture Echography and CT

Heart48,49,61,62 25 Atrioventricular or bundle branch block; ventricular tachycardia or brillation; congestive heart failure; pericarditis; impairment of sympathetic nerve activity; sudden death

Systematic electrocardiography, echocardiography, 24 h Holter monitoring, concentration of brain natriuretic peptide and pro-brain natriuretic peptide, MRI, perfusion scintigraphy, F-FDG PET, imaging of sympathetic innervation, biopsy is rarely done

Nervous system6365 ~5 Facial nerve palsy, optic neuritis, leptomeningitis, diabetes insipidus, hypopituitarism, seizures, cognitive dysfunction, de cits, hydrocephalus, psychiatric manifestations, spinal cord disease, polyneuropathy, small- bre neuropathy

CSF investigation, MRI, hormonal dose, electromyography, temperature-threshold testing; biopsy is rarely done

Kidney66 052 Rare symptoms; increased creatininemia sometimes associated with hypercalcaemia; nephrocalcinosis; kidney stones

Systematic renal tests, biopsy analysis

Parotitis1 4% Symmetrical parotid swelling, Heerfordts syndrome when associated with uveitis, fever, and facial palsy

Nose57 056 Nasal stu ness, nasal bleeding, crusting, anosmia Sinus CT, rhinoscopy, biopsy

Larynx57 051 Hoarseness, breathlessness, stridor, dysphagia Laryngoscopy, biopsy

Bones67

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secondary to lung brosis, localised bronchial stenoses, extrinsic compression, bronchiolitis, and airway hyper-reactivity.68 Pulmonary hypertension is caused by many mechanisms,80 and should be suspected when there are persistent dyspnoea insensitive to corticosteroids, pulmonary brosis, abnormal 6 min walk distance, reduced di usion capacity of carbon monoxide, a need for supplementary oxygen, or echocardiographic results suggestive of cor pulmonale. De nite diagnosis of pulmonary hypertension and exclusion of left ventricular dysfunction can only be con rmed with right heart catheterisation.52 Contrast CT is used to rule out pulmonary embolism, and helps to specify the mechanisms in pulmonary hypertension.80

3050% of patients show extrapulmonary disease localisations, which can sometimes be the major disease manifestation (table 1).57 Extrapulmonary localisations can be initial or occur later, and can be isolated symptoms or not. Extrapulmonary localisations should be detected with a thorough physical examination, in a systematic ophthalmological examination with a slit lamp, and with an electrocardiogram (ECG)61 and blood tests. The sarcoid origin of extrapulmonary localisations should then be assessed. Published criteria help to classify extrapulmonary

localisations as de nite, probable, or possible.57 Diagnosis is most di cult when only one organ is initially involved in uncommon localisations or when a biopsy is not possible.63 An occult localisation for biopsy sample might be found with the use of F-FDG PET.81

An international consensus58 has de ned categories for ocular manifestations from de nite to possible ocular sarcoidosis on the basis of presentation. The diagnosis of cardiac sarcoidosis, a potentially life-threatening localisation, is the most challenging without consensus.61 Manifestations include atrioventricular block, ventricular arrhythmias, congestive heart failure, sudden death, and consequences of impairment in sympathetic nerve activity. The presence of fragmented QRS or a bundle branch block pattern is associated with cardiac involvement.82 A myocardial biopsy sample that is positive is hard to obtain. Despite a revision in 2006, the Japanese Ministry of Health and Welfare guidelines do not include the most recent imaging investigations. Delayed-enhancement cardio vascular magnetic resonance identi es many more patients with cardiac sarcoidosis than do the Japanese Ministry of Health and Welfare guidelines for diagnosing cardiac sarcoidosis, and damage detected might be associated with future adverse

Figure 3: Imaging of various organ localisations in sarcoidosis(A) Fibrotic pattern of pulmonary sarcoidosis at CT. Characteristic features of severe architectural distortion with posterior volume loss and central traction bronchiectasis. (B) Cardiac sarcoidosis diagnosed on cardiac MRI shows subepicardial and transmural delayed enhancement on gadolinium-enhanced T1-weighted sequence. (C) FDG-PET and CT fusion image after dietary modi cations in the same patient reveals extensive focal uptake of the left ventricle. (D) Neurological involvement in sarcoidosis; typical involvement of hypothalamus, pituitary gland and optic chiasm seen on a sagittal gadolinium-enhanced T1-weighted sequence MRI (small arrow). Abnormal nodular enhancement of the fourth ventricle is also seen (arrow).

A B

C D

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cardiac events ( gure 3B).72 However, F-FDG PET could be the most reliable method for the detection of granulomatous myocardial lesions ( gure 3C).48,49

Neurosarcoidosis can involve all parts of the nervous system. However, central nervous system (CNS) diagnosis is de nite only in a minority of cases since neural biopsy is di cult to do.83 Features at presentation, MRI ( gure 3D), CSF analysis, ophthalmological examination, biopsy of extraneural organs, and other tests, often allow a probable diagnosis. Infections, multiple sclerosis, and neoplasms should be excluded.83 Diagnosis of spinal-cord sarcoidosis is di cult with discreet extraneurological signs in most cases.64,65 Small- bre neuropathy is recognised as a frequent, chronic, and disabling disorder.51,84 Peripheral pain, dysaesthesia, and various autonomic disturbances are the most common symptoms.84 Without a diagnostic gold standard for diagnosis of small- bre neuropathy, a screening list is useful.51

Another disabling symptom is fatigue, which occurs in up to 70% of patients, and can be measured and monitored with a validated fatigue assessment scale.85 This symptom is independent of disease activity, and is increased by dyspnoea, 6 min walk distance reduction, and muscular pain. Fatigue is multifactorial and can be caused by granuloma burden, weight gain and diabetes due to corticosteroid therapy, depression, sleeping disorders, hypothyroidism, and unknown factors.50 Cognitive failure is also a common problem in patients with sarcoidosis, irrespective of disease severity.86 Eventually, quality of life might be impaired,87 with fatigue, sleep, day-to-day activities, and working capacity all being a ected.

Tests of serum angiotensin-converting enzyme concentrations even after correction for a genetic insertion or deletion polymorphism that a ects serum concentrations,88 are not accurate for diagnosis of sarcoidosis. Chitotriosidase might be a better option for diagnosis.89 Reliable biomarkers of in ammatory activity are needed to manage patients with unexplained persistent symptoms that are disabling.46 Serum interleukin-2 receptor, neopterin, chitotriosidase,89 lysozyme, KL-6 and amyloid A90 are interesting biomarkers for assessing activity. Interleukin-2 receptor and neopterin predict F-FDG PET uptake, but they do not have a 100% sensitivity.46 Moderate and severe liver test abnormalities are associated with advanced histopathological changes.60 Abnormal creatininaemia should prompt searches for a renal localisation or nephrocalcinosis.66 The cause of thrombocytopeniaeg, splenomegaly, bone-marrow localisation, or immuneshould be investigated.91 Hypercalcaemia is most common in white men older than 40 years of age; during the summer; and hypercalcaemia is less common than hypercalciuria, a cause of kidney stones.66 Assessments of the concentrations of plasma N-terminal pro-brain natriuretic peptide and troponin T are useful for the diagnosis of cardiac sarcoidosis.92,93

MonitoringClinical course and prognosisThe clinical course for sarcoidosis varies (appendix p 3). In half of cases, disease resolves spontaneously within 2 years, and does so in many other cases within 5 years. After 5 years, remission is much less likely.1,31,94 These di erent outcomes have led to the classi cation of sarcoidosis into acute (2 years) and chronic (35 years) phenotypes.1,31,94 Refractory sarcoidosis refers to patients progressing despite treatment.3 The main concerns with chronic sarcoidosis are brosis (pulmonary and extrapulmonary), pulmonary hypertension, and persistent disabling symptoms and impaired quality of life.

Several indicators of prognosis have been reported (appendix p 4).1,31,94 There is an inverse relation between radiographical stage at presentation and the probability of spontaneous recovery. Several investigators have attempted to devise a comprehensive scoring system to assess severity of disease.3,95,96 Two scores have been reported that integrate whether treatment is needed, and whether the treatment should last for more than 12 months.3,95 However, neither score has been prospectively validated. Serum concentrations of interleukin-2 receptor, neopterin, and chitotriosidase might be markers of sarcoidosis activity and progression,88,97 but their value in routine practice has not been de ned clearly.98

Follow-upThe modalities and duration for monitoring patients with sarcoidosis during follow-up have not been standardised. A general guide should be: clinical examination and chest radiograph every 36 months, pulmonary function tests, ECG and blood tests that include serum creatinine and calcium concentrations measurements every 6 months. An accurate de nition of change in pulmonary sarcoidosis might be di cult.99 Changes in chest radiographs can help to diagnose pulmonary exacerbations,99,100 and to exclude any complications or comorbidities; however, pitfalls with this technique72 can be countered with the simultaneous use of pulmonary function tests and taking into account symptoms. Measurement of serial serum angiotensin-converting enzyme has no established role in the monitoring of sarcoidosis.98

Although disease relapse in patients with spontaneous remission is rare (8%), 3774% of treated patients have exacerbation or relapse when corticosteroids are tapered or discontinued.101 Relapses mostly occur 26 months after corticosteroid withdrawal, and are rare after 3 years without symptoms.101 This fact justi es a minimum 3 year follow-up after the end of treatment before recovery can be con rmed,101 consequently, the involvement of originally una ected organs should raise the possibility of an associated comorbidity. Pregnancy does not usually interfere with sarcoidosis, but a are up is not uncommon shortly after delivery.102

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Morbidity and mortalityAbout 20% of patients have permanent clinical symptoms because of irreversible brosis, mainly pulmonary brosis.1 Around 12% of all stage 4 patients need long-term oxygen therapy, and many develop diverse complications, including pulmonary hypertension (297%) and aspergilloma (113%).103

Patients with sarcoidosis have a lower survival rate than do the general population.103105 Premature death is most often due to sarcoidosis itself. Strikingly, in the previous two decades, sarcoidosis-related mortality has increased, particularly in patients aged 5574 years.105 Mortality is reported to be up to 76%.105 In western countries, most fatalities from sarcoidosis are due to advanced pulmonary brosis and less commonly, cardiac, CNS and hepatic involvement.1 Most decedents with stage 4 disease (687%) die from respiratory failure or pulmonary hypertension or both. Other causes of death include haemoptysis from aspergilloma.103 Pulmonary hypertension is the most robust predictor of mortality in patients who are candidates for lung transplantation106 and in unselected stage 4 patients.103 Precapillary pulmonary hypertension is associated with increased mortality compared to no pulmonary hypertension or pulmonary hypertension with left-ventricular dysfunction.52 In Japan, the main cause of mortality is cardiac involvement, which is accountable for 77% of deaths in people with sarcoidosis. Sarcoidosis can also be associated with increased incidence of lymphoma, and be a risk factor for pulmonary embolism.107

Treatment There is no cure for sarcoidosis, and treatment only changes the granulomatous process and its clinical consequences. The mechanisms of action for drugs that are used in sarcoidosis are only partly understood (table 2). Most drugs target TNF, which has a crucial role in the initiation and perpetuation of the granulomatous response. Debate exists about whether treatment can change the outcome of sarcoidosis, particularly brosis.1 No rm guidelines exist on whether, when, and how treatment should be started.117 Between 20% and 70% of patients need systemic therapy.1,101,118 The decision to treat either immediately or during follow-up is guided by three broad factors: risk of severe dysfunction or irreversible damage to major organs, risk of death, or the presence of incapacitating, constitutional symptoms. The main indications for treatment are involvement of the cardiac, neurological, or renal systems; ocular sarcoidosis that does not respond to topical therapy; and symptomatic hypercalcaemia (appendix p 6).1,2

The best strategy would be to observe newly diagnosed patients that have a high probability of spontaneous resolution, and to decide on a treatment when the disease progresses with concordant radiographical and functional progression in the lung. In terms of evidence-based treatment for sarcoidosis, only a few randomised controlled trials have been done: 13 of corticosteroids,119

and ve of immunosuppressive and cytotoxic therapy,120 and ve other randomised controlled trials.31,121123 A pressing need exists for the de nition of clinically appropriate endpoints for treatment response.98

Systemic corticosteroids remain the standard treatment (appendix p 6). No clear protocol has been validated for dose and treatment duration (table 2).124 Initial treatment is often prednisone 2040 mg daily for 612 weeks, with the dose reduced after this time. In some life-threatening situations such involvement of the heart, CNS, and kidney, or severe ophthalmological localisations, the initial dose is 1 mg/kg daily. Although a minimum of 12 months of maintenance therapy is often advised to prevent relapse, several investigators think that treatment should be stopped as early as 6 months after initiation.124 Adjustments to treatments should be made according to clinical presentation. Patients with chronic sarcoidosis might need low-dose treatment for many years, whereas treatment for 36 months might be adequate for patients with acute forms of disease.

Although systemic corticosteroid treatment for symptomatic sarcoidosis has short-term bene ts, there is little evidence for long-term e ect. Evidence from a meta-analysis119 supported that corticosteroid resulted in improvement signs on chest radiographs in patients with stage 2 and stage 3 disease after 624 months of treatment, and slightly improve the forced vital capacity by 42%, and di usion capacity of carbon monoxide by 57%. Whether or not asymptomatic patients with persistent lung in ltration should be given systemic treatment is unresolved.2,118,125

The increased awareness of long term side-e ects of corticosteroids, and the emergence of new drugs, has changed the treatment of sarcoidosis. Alternative or additional options to corticosteroids should be assessed under various circumstances: involvement of speci c organs, contraindication for corticosteroids, a need for a corticosteroid-sparing therapy, and corticosteroid-resistant disease (table 2; appendix p 6). Antimalarial drugs or tetracyclines might be preferable to corticosteroids for mild skin involvement, and antimalarial drugs are preferred for mild hypercalcaemia.1,2 Conventional cortico steroid-sparing drugs are antimalarial drugs,125 metho trexate,126 or azathioprine.109 Methotrexate is more commonly used for corticosteroid-resistant disease than is azathioprine.2 In a Delphi survey,108 methotrexate was the second-choice treatment for most physicians specialising in sarcoidosis. However, because methotrexate has a delayed e ect, it has to be used with corticosteroids when both a rapid e ect is needed for sarcoidosis that involves vital organs and a prolonged course of disease is anticipated. Results of two retrospective uncontrolled studies suggest that le unomide might enable reduction of corticosteroid dose,110 and that it might be e cient alone or when used with methotrexate in pulmonary and other extrapulmonary localisations that have a poor response with therapy or if there are toxic e ects from the previous treatment.110,127

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About 10% of patients with chronic sarcoidosis will still have active disease despite being given at least one immunosuppressant drug.3 In the past 10 years, TNF antagonists were used increasingly as the treatment of chronic sarcoidosis. In iximab showed e cacy in a randomised controlled trial compared with placebo in a population with pulmonary refractory sarcoidosis.31 However, the improvement in forced vital capacity was

only 25%, and there was no gain in St Georges Respiratory Questionnaire dyspnoea score, and 6 min walk distance.31 Post-hoc exploratory analyses report that patients with long-lasting disease, lower forced vital capacity, higher St Georges Respiratory Questionnaire total score, greater dyspnoea,31 or increased C-reactive protein,128 at baseline bene t more from treatment than do those given placebo. In iximab was also e cacious

Usual dose Main contraindications Main side-e ects Monitoring needed Comments

Corticosteroids

Prednisone 2040 mg/day initially*, 510 mg/day (or equivalent alternate-day dosing) for maintenance treatment

Unstable psychiatric disorder

Weight gain, hypertension, osteoporosis, diabetes, infection, neuropsychiatric reactions

Weight, arterial blood pressure, glycaemia, bone density

The most e ective, rapid-acting, and available drug. First-line treatment for severe sarcoidosis

Cytotoxic drugs

Methotrexate 1020 mg once per week orally or intramuscularly. Folate supplementation to prevent gastrointestinal toxic e ects

Liver and severe renal failure; severe respiratory failure; alcohol abuse; pregnant or lactating women

Gastointestinal e ects, neutropenia, liver and renal toxicity, interstitial pneumonitis, alopecia

Complete blood count liver function tests, and renal function every 412 weeks

Preferred second-line therapy for corticosteroid-resistant sarcoidosis or as a corticosteroid-sparing drug.108 Delayed e ect (up to 6 months)

Azathioprine 50200 mg per day Lactating women; association with allopurinol

Gastrointestinal e ects, neutropenia, liver toxicity, photosensitivity, skin carcinoma

Complete blood count and liver function tests every 412 weeks; consider thiopurine S-methyltransferase genotyping

Similar comments as methotrexate but fewer data are available.109 can be used in men and women who want to have children, and used during pregnancy

Le unomide 1020 mg per day Liver and renal failure; bone marrow dysfunction; pregnant or lactating women

Gastrointestinal e ects, diarrhoea, liver toxicity, neutropenia, neuropathy, hypertension

Complete blood count and renal function tests every 412 weeks

Insu cient data: might be useful in patients not responding well or who are intolerant to methotrexate or as a corticosteroid-sparing drug.110 Combination treatment with methotrexate is possible, fewer pulmonary toxic e ects than with methotrexate

Cyclophosphamide 50150 mg per day orally; or 5001200 mg every 34 weeks intravenous pulse

Severe renal failure; bone marrow dysfunction; pregnant or lactating women

Neutropenia, gastrointestinal e ects, haemorrhagic cystitis, possible irreversible sterility in both men and women, increased risk of malignancy, mostly bladder cancer

Complete blood count liver function tests and renal function tests every 24 weeks

Potentially serious side-e ects that restrict its use; might be useful for refractory CNS83 and cardiac involvement; rapid e ect

Mycophenolate mofetil 5003000 mg per day Pregnant (insu cient data on teratogenicity) or lactating women

Neutropenia, gastrointestinal e ects, diarrhoea, photosensitivity, skin carcinoma

Complete blood count and liver function tests every 412 weeks

Insu cient data, might be useful as a corticosteroid-sparing drug.111 Fewer bone marrow toxic e ects and infections than other immunosuppressant drugs

Cytokine modulators

Pentoxifylline 4002000 mg per day Acute myocardial infarction

Nausea, diarrhoea, gastrointestinal e ects

None Insu cient and con icting data; might be useful as a corticosteroid-sparing drug.112 At the dose used, gastrointestinal toxic e ects are very restraining112,113

Thalidomide 50200 mg per day Men refusing to wear a condom and women of childbearing age not using contraception; pregnant or lactating women; blood donation

Highly teratogenic; sleepiness, constipation, neuropathy, venous thrombosis, unexplained dyspnoea, bradycardia

Pregnancy testing every month and electromyography every 612 weeks

Potentially serious side-e ects; useful for severe skin sarcoidosis, particularly lupus pernio; not e ective for pulmonary involvement;114 rapid e ect; as early as 1 month

TNF antagonist In iximab 35 mg per kg intravenously at week 0, 2, 6, then every 48 weeks

Pregnant (insu cient data on teratogenicity) or lactating women; New York Heart Association class 3 or 4 heart failure; tuberculosis or other infection

Allergic reaction. Increased risk of serious infections, mostly tuberculosis, and increased risk of cancer

Systematic assessment for tuberculosis before treatment

Useful for chronic and refractory sarcoidosis particularly in lupus pernio, eye, and CNS disease.115 E cacy for pulmonary disease,31 but whether improvement is clinically relevant is debated. Rapid e ect; as early as 2 weeks. Possible loss of response due to anti-in iximab antibody formation

(Continues on next page)

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for extrapulmonary sarcoidosis assessed as a secondary endpoint of the trial, but improvements during the 24 weeks of treatment were lost in the subsequent 24 week washout. Data from retrospective studies lend support to the expectation that a response with in iximab is valuable for some patients, mainly those with CNS115,129 or eye115 recalcitrant involvement, and lupus pernio.115,130 However, the advantage with biological therapy should be tempered by potentially serious toxic e ects. By contrast, etanercept is ine ective in progressive pulmonary131 and ocular disease.121 Adalimumab is e cacious in uveitis, as well as other disabling symptoms related to sarcoidosis.132 Rituximab is e cacious in refractory ocular lesions.133 Apremilast has been e cient in di cult-to-treat skin localisations.134 Dexmethyl-phenidate is superior to placebo for the treatment of fatigue, which is an otherwise di cult therapeutic issue.123 However, dexmethylphenidate is an amphetamine psychostimulant that should be prescribed with caution. Combination treatments might act at several levels of disease pathogenesis and have fewer toxic e ects.

Topical corticosteroids are helpful for the treatment of eye and skin involvement. Although useful for cough and bronchial hyper-reactivity, treatment with inhaled corticosteroids alone do not objectively improve the results in pulmonary function tests or radiograph images.119 Sequential treatment with 3 months of oral prednisone followed by 15 months of inhaled budesonide resulted in a signi cant, but small, long-term, functional improvement in patients with recent stage 2 or stage 3 disease.125

In addition to speci c treatments, symptomatic and supportive measures are crucial, including reducing intake of calcium and sun avoidance for hypercalcaemia,

drugs and implantable devices for cardiac involvement, hormonal substitution for hypothalamicpituitary involvement, and supplemental oxygen.1 Pulmonary rehabilitation has not been assessed. The bene t and safety of drugs used for sarcoidosis-related pulmonary hypertension are not established, and might depend on an underlying primary mechanism.135 Endobronchial stenosis can necessitate mechanical dilatation. Antifungal treatment for aspergilloma is controversial, and surgical removal might be problematic in patients with severe pulmonary brosis. In patients with corticosteroid-induced osteoporosis, it is sensible to measure serum and urinary calcium concentrations before and periodically after the start of calcium and vitamin D supplementation. Bisphosphonate treatment should be chosen as the initial strategy for primary prevention of corticosteroid-induced osteoporosis.136

Despite disease-speci c issues, transplantation of the lung, liver, heart, or kidney is a reasonable option for end-stage sarcoidosis, with results generally matching those of other diagnoses.137 Referral should be made only after medical treatment options have been exhausted, and the disease extent, severity, and activity must be carefully assessed. The presence of aspergilloma should not disqualify potential transplant candidates.137 Recurrence of sarcoidosis in the allograft is 1435%, and is usually not di cult to control with medical treatment.137,138

ConclusionsSarcoidosis has many manifestations, its prognosis is di cult to predict, and its evolution and severity vary hugely from case to case. A personalised and multidisciplinary approach might be needed to address these challenges and prevent quality-of-life impairment and potential adverse e ects of treatment.

Usual dose Main contraindications Main side-e ects Monitoring needed Comments

(Continued from previous page)

Antimicrobial drugs

Antimalarial drugs Hydroxychloroquine 200400 mg/day||

Retinopathy, breastfeeding

Gastrointestinal e ects, rash, retinopathy, neuromyopathy

Complete eye examination every 612 months

Inhibit antigen presentation by reducing degradation capacity of lysosomes; useful for moderate skin disease; hypocalcaemia, and fatigue, as well as a corticosteroid-sparing drug;116 delayed e ect up to 6 months

Tetracycline Minocycline 200 mg/day, doxycycline 200 mg/day

Pregnancy and breastfeeding, liver failure, sun exposure

Gastrointestinal e ects, anaemia, skin photosensitivity

None Few data: might be useful for moderate skin disease

*1 mg/kg per 24 h of prednisone might be necessary to control cardiac and CNS disease. High-dose intravenous pulse methylprednisolone might be useful in patients with sarcoidosis that threatens life or organ function, such as in severe cardiac, CNS, laryngeal and renal involvement, or retrobulbar neuritis. All cytotoxic drugs are potentially teratogenic, with the exception of azathioprine. All drugs increase the risk of infection and malignancy. The risk of infection is especially increased with TNF antagonists, and the risk of malignancy with cyclophosphamide. The view that liver biopsy should be done after a cumulative dose of methotrexate of more than 12 g to exclude subclinical toxicity is controversial and non-invasive analysis of liver brosis might be replace liver biopsy. Although thiopurine S-methyltransferase (TPMT) de ciency is rare, individuals can develop severe pancytopenia due to azathioprine not being correctly metabolised. Genotyping of TPMT is available and might be helpful to predict patients who will develop toxicity. This sensitivity to azathioprine needs to be identi ed with the introduction of the drug at 50 mg per day and close monitoring of complete blood count, and should be closely monitored, especially in the rst month of treatment. In iximab is the preferred TNF antagonists. In some patients, the bene t of in iximab is lost within 6 months of discontinuing the drug after 24 weeks of treatment, so most physicians prescribe the drug for a longer time. Adalimumab is another treatment, but much fewer data are available. Etanercept is not e ective in sarcoidosis. ||Hydroxychloroquine is preferred to chloroquine because of the lower risk of ocular toxicity. TNF=tumour-necrosis factor-. CNS=central nervous system.

Table 2: Drugs used in sarcoidosis

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ContributorsDV outlined the Seminar, collected and edited the di erent sections of the draft, and wrote the diagnosis section. AP and JM-Q wrote the pathogenesis section. HN wrote the monitoring and treatment sections. YU, DV, HN, JM-Q, and AP searched for clinical aspects and pathophysiology. P-YB provided the gures. All the authors reviewed the Seminar and approved the nal version.

Con icts of interestDV has received scienti c advisor consultancy fees from Sano , InterMune, and Actelion; travel and accommodation expenses to attend the American Thoracic Society conference and European Respiratory Society congress, the Congrs de Pneumologie de langue Franaise, and international meeting for orphan diseases 2011 from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Mundipharma, and Actelion; as well as academic grants from Direction de la Recherche Clinique and the Chancellerie des universits de Paris. DV has served as investigator or member of the steering committee for INSPIRE, CAPACITY, BUILD 1, and BUILD 3, and was an investigator in the Centocor (Jansen Biotech)-funded trial evaluating golimumab versus placebo in severe sarcoidosis. The other authors declare that they have no con icts of interest.

AcknowledgmentsWe thank Emmanuelle Blondet (Haute Autorit de Sant, Saint-Denis, France) for assistance with the search strategy and selection criteria, and thank Gabrielle Kaufman and Sven Lord for assistance with English language editing.

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SarcoidosisIntroductionEpidemiologyPathogenesisCausesInflammatory mechanismsGranuloma formationGenetics

DiagnosisMonitoringClinical course and prognosisFollow-upMorbidity and mortality

TreatmentConclusionsAcknowledgmentsReferences

Sarcoidosis Lancet 2013

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